PROJECT SUMMARY Measures of functional magnetic resonance imaging (fMRI) functional connectivity ? correlated blood oxygen level dependent (BOLD) responses ? are fundamental to understanding the circuit-level mechanisms of brain function and dysfunction. The use of fMRI functional connectivity for understanding long-range dynamic interaction between areas is limited, however, because the physiological basis of this measure is unknown. This is because our knowledge is limited to correlative relationships between neural activity and BOLD functional connectivity. Nothing is known about the causal relationship between neural activity and fMRI measures of functional connectivity. In addition almost nothing is known about mechanisms of fMRI based functional connectivity outside of sensory areas. We propose to causally investigate the relationship between the disruption of a specific pathway and changes to both neural and BOLD coherence in the same animals. We will address this question in a limbic-prefrontal pathway as emerging data suggests dissociations between neural activity and fMRI in limbic structures. We will use a translationally-relevant behavioral task, probabilistic reversal learning, that is known to be dependent on interaction between prefrontal and limbic structures. We will use a multi-dimensional approach, combining high-resolution multi-echo fMRI, high-density neurophysiology recordings of single neurons and local field potentials (LFP) and pathway specific manipulations of neural activity in macaque monkeys, the best available model of human limbic and prefrontal cortex. We will directly inhibit the projections from the limbic system to prefrontal cortex using a pathway- specific chemogenetic approach and assess the effects on both resting state and task-based functional connectivity. Our approach will lead to a causal understanding of how fMRI functional connectivity and neural activity are related to each other at rest and during cognition. Gaining this knowledge is important, as it would define the neural basis for this widely used fMRI measure. This will aid basic research on the brain as well as potentially help therapeutic approaches that aim to alter activity in distributed brain circuits. !